HIV-caused AIDS is a potentially lethal disease with no vaccine or cure available at the moment. The obstacles to overcome when developing an effective HIV vaccine include devising a strategy that would generate cellular and humoral immunity with sufficient a) strength to be 'virus- replication-clobbering'and b) breadth to address the extraordinary genetic diversity of the virus. Our proposal is focused specifically on increasing the 'immunizing strength'of HIV vaccines. For this purpose we have developed highly immunogenic recombinant attenuated Listeria vaccine vectors and recombinant Lactococcus lactis vaccine particles. Antigenic priming and boosting with these new vaccine-delivery systems elicits remarkable T-cell and Ab responses. In addition, we have demonstrated that a nonpeptidic phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) together with interleukin-2 stimulate prolonged expansion of V32V42 T effector cells in the lymphoid and mucosal compartments and enhance 12 T-cell and antibody responses. Here we propose studies to ascertain whether or not the strong immunoadjuvant effect of V32V42 T-cell stimulation can be utilized in increasing the 'immunizing strength'of HIV vaccines. Specifically, we propose to test our hypothesis that V32V42 T effector cells generated after HMBPP/IL-2 treatment can readily traffic to the lymphoid tissues and mucosae and upregulate the breadth and magnitude of HIV vaccine-elicited T-cell and antibody responses and ultimately increase the vaccine's protective effects against HIV/AIDS. Thus, our main specific aim is to determine whether the V32V42 T-cell-activating/expanding treatment with HMBPP plus IL-2 can augment the anti-SHIV89.6P potency of our attenuated Listeria ?actA prfA* vaccine vectors expressing HIV-1 Env and SIV gag in SHIV89.6P-challenged rhesus macaques. PUBLIC HEALTH RELEVANCE: There is no vaccine or cure for HIV/AIDS, which is a potentially lethal disease. The main focus of this application is to test a novel strategy for boosting the capacity of HIV vaccines to induce protective responses against HIV/AIDS. Even partial success may have worldwide beneficial effect.